Vesalius Research Center, VIB and K.U. Leuven, Campus Gasthuisberg, Leuven, Belgium.
Nat Med. 2011 Jul 24;17(8):968-74. doi: 10.1038/nm.2396.
Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.
遗传性运动感觉神经病（CMT）是最常见的周围神经系统遗传疾病。27kDa 小热休克蛋白基因（HSPB1）的突变导致轴索 CMT 或遗传性远端运动神经病（distal HMN）。我们开发并鉴定了仅在神经元中表达两种不同 HSPB1 突变（S135F 和 P182L）的转基因小鼠。这些小鼠表现出依赖于突变的 CMT 或遗传性远端运动神经病的所有特征。突变型 HSPB1 的表达降低了乙酰化α-微管蛋白的丰度，并诱导严重的轴突运输缺陷。通过组蛋白去乙酰化酶 6（HDAC6）的药理学抑制诱导的α-微管蛋白乙酰化增加纠正了 HSPB1 突变引起的轴突运输缺陷，并挽救了有症状的突变 HSPB1 小鼠的 CMT 表型。我们的研究结果表明α-微管蛋白去乙酰化在突变 HSPB1 诱导的神经病变中的致病作用，并为使用 HDAC6 抑制剂作为遗传性轴突病变的治疗策略提供了新的视角。
